1. Field of the Invention
Dimethyl 5-nitro-isophthalate is an important intermediate for preparing radiopaque media for intravenous administration which comprise, as X-ray-absorbing component, derivatives of 5-amino-2,4,6-triiodo-isophthalic acid. Other dialkyl 5-nitro-isophthalates may be used similarly. There is a considerable demand for such intermediates which should be obtainable at the lowest possible cost and, at the same time, in high purities. In the pharmaceutical sector, even intermediates have to be at least 99.5% pure with respect to by-products, and a particular by-product may generally be present at the most at 0.3%.
2. Discussion of the Background
A plurality of synthetic routes for preparing dimethyl 5-nitro-isophthalates are already known; however, none of them is satisfactory. According to J. Org. Chem. 26, 2963 (1961) and U.S. Pat. No. 2,680,730, dimethyl isophthalate is dissolved in concentrated or fuming sulfuric acid and nitrated using a mixture of sulfuric acid and nitric acid. The desired compound is obtained as main component; however, during the nitration (as has been found by our own experiments), not insignificant amounts of the undesirable isomeric dimethyl 4-nitro-isophthalate are formed. Additionally, variable amounts of monomethyl 5-nitro-isophthalate are formed by hydrolysis during work-up when the reaction mixture is discharged onto ice (see Example 9). The resulting product is by no means pure enough for the above-mentioned use in pharmaceutics. The product has to be purified by recrystallization, and considerable losses of yield occur. The above-mentioned literature states that the desired product is obtained in a yield of only 42% of theory. Even the recrystallized product is not yet sufficiently pure, as becomes evident when the melting point of this product (119-121.degree. C.) is compared with the melting point of the pure product (123.degree. C.).
According to Ber. 43, 3474 (1910) and Pharmazie, 21 (3), 167-170 (1966), dimethyl 5-nitro-isophthalate can also be obtained by esterifyng 5-nitro-isophthalic acid with a large excess of methanol (for example 33 mole of methanol/mole of 5-nitro-isophthalic acid) in the presence of sulfuric acid. In this reaction, initially the monomethyl ester and then from this the dimethyl ester is formed, which crystallizes out from the solution. However, the product which is obtained is not pure enough for pharmaceutical applications, since it comprises 0.3 to 0.5% of the monomethyl ester. Here, the product likewise has to be purified by recrystallization and the above-mentioned disadvantages have to be accepted.
The esterification of 5-nitro-isophthalic acid with diazomethane (see Indian Drugs & Pharmaceutical Industry, November/December 1980, p. 35 ff.) is also not satisfactory, since diazomethane is very toxic and carcinogenic and, owing to its high instability, can only be handled on an industrial scale if very costly safety measures are taken. A diazomethane-based production process can therefore not be carried out economically. Thus, it is not surprising that the same authors describe, in the same publication, a further process where 5-nitro-isophthalic acid is initially converted, using thionyl chloride, into its acid chloride which, after intermediate isolation, is reacted with methanol to give the desired ester. To this end, large excesses of reagents have to be employed. Moreover, very long reaction times are required (for example 48 h just for forming the acid chloride). The resulting product is not pure, and once again, it has to be purified by recrystallization, with the above-mentioned disadvantages, so that altogether three process steps are required. This complicated synthesis likewise gives the desired product in only unsatisfactory yield. Likewise, this process does not allow an economical preparation of the desired product. Another known process for the esterification of carboxylic acids is the esterification by means of dialkyl sulfate. According to the more recent prior art (EP-A 757 028), the esterification is carried out in the presence of a water-insoluble tertiary amine and water, if appropriate in the presence of a water-insoluble solvent, with addition of a base at a pH of 5 to 12. A disadvantage of this process is the use of extremely carcinogenic dialkyl sulfates. Apparently, it is not possible to prepare dimethyl 5-nitro-isophthalates in this manner. This may be due to the fact that, according to the EP-A, the resulting esters are generally worked up by distillation (in which see p. 3, line 19), which is not possible for dimethyl 5-nitro-isophthalate since even its melting point is high (123.degree. C.) and nitro compounds do not withstand considerable thermal stress.